We have previously reported that murine antihuman monoclonal antibody OKT3 (Orthoclone OKT3) given for 14 days after heart transplantation is effective as immunosuppressive prophylaxis. The optimal protocol for OKT3 prophylaxis in heart transplantation is unknown, particularly the duration of OKT3 therapy. We conducted a consecutively allocated overlapping 6-month study with 68 heart transplant patients, comparing 14-day OKT3 (n = 34) to 10-day OKT3 treatment (n = 34). Both protocols included OKT3 given beginning 24 to 48 hours after operation, cyclosporine beginning on postoperative day 3, low-dosage steroids and azathioprine to prevent antibody production to OKT3, and a steroid pulse plus randomization to plus or minus vincristine after stopping OKT3. Pretransplant characteristics including age, sex, cause of congestive heart failure, and absence of positive pretransplant crossmatch were similar between the two groups. Although the infection rate was not significantly different between the two groups and mortality (one patient in each group) did not differ, 14-day prophylaxis decreased the number of treated rejection episodes per patient for the 6-month study (1.59 +/- 0.18 versus 2.24 +/- 0.19, p = 0.016). A 14-day course of OKT3 also decreased the risk of rejection during the 6-month follow-up period (p less than 0.05). In addition to having a decreased number of rejection episodes, patients in the 14-day protocol were also more likely to be withdrawn from maintenance steroids (79% versus 53%, p = 0.02). In conclusion, a measurable dose response efficacy can be demonstrated for 14-day versus 10-day OKT3 prophylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)